Systematic Characterization of Small Nucleolar RNAs in Cancer
癌症中小核仁 RNA 的系统表征
基本信息
- 批准号:10914508
- 负责人:
- 金额:$ 41.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:Antisense OligonucleotidesAttenuatedBiologicalBiological MarkersBiological ModelsBiomedical ResearchBreast Cancer CellBreast Cancer cell lineCancer PatientCell ProliferationClinicalCommunitiesComputing MethodologiesDataDevelopmentDiagnosticDrug resistanceExhibitsFDA approvedFatty acid glycerol estersFoundationsFutureGeneticGenetic TranscriptionGoalsGrowthIn VitroIndividualInvadedMalignant NeoplasmsMammary TumorigenesisMammary glandMolecularMultiomic DataOutcomePathway interactionsPatient-Focused OutcomesPatientsPharmaceutical PreparationsPlayProcessPrognosisProliferatingQuantitative Trait LociRNARNA-targeting therapyResearchResearch PersonnelRoleSamplingSignal PathwaySignal TransductionSmall Nucleolar RNASolid NeoplasmSystemThe Cancer Genome AtlasTherapeuticTranscription AlterationWorkXenograft procedurecancer drug resistancecancer initiationcancer subtypescancer typeclinically relevantclinically significantdata portaldata resourcedeep learningdiagnostic valuedifferential expressiondisease diagnosticdrug response predictioneffective therapygenetic variantimprovedin vivoindividual responseinsightlarge scale datamalignant breast neoplasmmammarymouse modelnovelprognosticprognostic valuerefractory cancerresponsesuccesssurvival outcometargeted cancer therapytargeted treatmenttherapeutic RNAtherapeutic targettreatment strategytriple-negative invasive breast carcinomatumortumorigenesisuser-friendly
项目摘要
Abstract
Despite recent advancements in treatment options for cancer, a majority of cancer types continue to lack fully
characterized and effective targeted therapies. This insufficiency has resulted in the demand for alternative,
previously unconsidered treatment approaches to improve disease diagnostics, prognoses, and patient
survival outcomes. Recently, we performed integrative analysis for small nucleolar RNA (snoRNAs) in a large
number of patient samples and identified 46 snoRNAs that exhibit broad-spectrum clinical significance with 12
or more types of cancer. We developed a data portal, snoRNA in cancers (SNORic), which allows researchers
to explore the significance of individual snoRNAs in cancer. SNORic has been accessed >100,000 times since
its release in 2017, suggesting its broad impact in the biomedical research community. We provided initial
genetic evidence indicating that elevated expression of snoRNAs facilitated the tumorigenesis of mammary
gland malignancies. Mechanistically we demonstrated that SNORD46 plays important roles in promoting the
initiation, growth, invasion and progression of TNBC. Therefore, elucidation of the roles of snoRNAs in
promoting tumorigenesis serves as the first step in the development of a novel class of snoRNA-based
biomarkers and therapeutic targets.
Our central hypothesis is that snoRNAs serve as essential RNA targets in promoting cancer initiation,
progression, and drug resistance, which could be attenuated in vivo by an antisense oligonucleotide-based
targeted therapy. In specific aim 1, we will delineate the diagnostic and prognostic values of these snoRNAs in
triple-negative breast cancer (Aim 1.1). We will demonstrate the molecular mechanism that these snoRNAs
promote TNBC cell proliferation, mobility and invasion (Aim 1.2). We will demonstrate that antisense
oligonucleotide-based snoRNA targeted therapy effectively inhibits TNBC growth in vivo (Aim 1.3). We will
evaluate and interpret causal effects through molQTL analysis (Aim 1.4). In specific aim 2, we will determine
the role of three snoRNAs in breast cancer drug resistance (Aim 2.1). We will understand the molecular
mechanisms for drug resistance through multi-omics data (Aim 2.2). To expand our perspective on drug
resistance, we will predict the drug response from individual snoRNA expression with the augmentation of
deep learning (Aim 2.3). We will study the drug responses effects among snoRNA-based subtypes (Aim 2.4).
We will build a user-friendly data portal for releasing the date generated through integrative analysis (Aim 2.5).
This study will significantly advance the prognostic, diagnostic, and therapeutic potential of snoRNAs; the
absence of this research work will greatly hinder the realization of snoRNA-based therapeutic considerations
for cancer patients.
摘要
尽管最近在癌症的治疗选择方面取得了进展,但大多数癌症类型仍然缺乏充分的治疗。
特征和有效的靶向治疗。这种不足导致了对替代品的需求,
以前未考虑的治疗方法,以改善疾病诊断,诊断和患者
生存结果。最近,我们进行了整合分析的小核仁RNA(snoRNA)在一个大的,
许多患者样品,并鉴定了46种snoRNA,其表现出广谱临床意义,其中12种具有广谱临床意义。
或更多类型的癌症。我们开发了一个数据门户网站,癌症中的snoRNA(SNORic),
探索单个snoRNA在癌症中的意义。SNORic自发布以来已被访问超过100,000次
它于2017年发布,表明其在生物医学研究界的广泛影响。我们提供了初始
遗传学证据表明,snoRNA的表达升高促进了乳腺癌的发生,
腺体恶性肿瘤从机制上讲,我们证明了SNORD 46在促进
TNBC的起始、生长、侵袭和进展。因此,阐明snoRNA在
促进肿瘤发生是开发一类新的基于snoRNA的肿瘤抑制剂的第一步。
生物标志物和治疗靶点。
我们的中心假设是snoRNA作为促进癌症发生的重要RNA靶点,
进展和耐药性,这可以通过基于反义寡核苷酸的
靶向治疗在具体的目标1中,我们将描述这些snoRNA在以下疾病中的诊断和预后价值:
三阴性乳腺癌(目标1.1)。我们将展示这些snoRNA的分子机制,
促进TNBC细胞增殖、迁移和侵袭(目的1.2)。我们将证明反义
基于多核苷酸的snoRNA靶向疗法有效地抑制体内TNBC生长(目标1.3)。我们将
通过molQTL分析评估和解释因果效应(目标1.4)。在具体目标2中,我们将确定
三种snoRNA在乳腺癌耐药性中的作用(目标2.1)。我们将了解分子
通过多组学数据研究耐药机制(目标2.2)。扩大我们对毒品的看法
耐药性,我们将预测药物反应,从个别snoRNA表达的增强,
深度学习(目标2.3)。我们将研究基于snoRNA的亚型之间的药物反应效应(目的2.4)。
我们将建立一个方便用户的数据门户网站,以发布通过综合分析产生的数据(目标2.5)。
这项研究将显着提高snoRNA的预后、诊断和治疗潜力;
缺乏这项研究工作将极大地阻碍基于snoRNA的治疗考虑的实现
for cancer癌症patients病人.
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Harnessing transposable elements for cancer therapy.
利用转座元件进行癌症治疗。
- DOI:10.1016/j.trecan.2023.05.005
- 发表时间:2023
- 期刊:
- 影响因子:18.4
- 作者:Liu,Yuan;Han,Leng
- 通讯作者:Han,Leng
Dynamic immune signatures as biomarkers for irAEs.
- DOI:10.1016/j.trecan.2023.03.004
- 发表时间:2023-03
- 期刊:
- 影响因子:18.4
- 作者:Jingwen Yang;Ya-Min Chen;Leng Han
- 通讯作者:Jingwen Yang;Ya-Min Chen;Leng Han
Spatial landscape of the tumor immune microenvironment.
肿瘤免疫微环境的空间景观。
- DOI:10.1016/j.trecan.2023.03.006
- 发表时间:2023
- 期刊:
- 影响因子:18.4
- 作者:Chen,Yamei;Liu,Yuan;Han,Leng
- 通讯作者:Han,Leng
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Leng Han其他文献
Leng Han的其他文献
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{{ truncateString('Leng Han', 18)}}的其他基金
Characterization of Alternative Polyadenylation in Alzheimer's Disease
阿尔茨海默病中替代多腺苷酸化的表征
- 批准号:
10321676 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
MolQTL: A comprehensive resource for molecular quantitative trait loci in human cancer.
MolQTL:人类癌症分子数量性状位点的综合资源。
- 批准号:
10593169 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
MolQTL: A comprehensive resource for molecular quantitative trait loci in human cancer.
MolQTL:人类癌症分子数量性状位点的综合资源。
- 批准号:
10427368 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
MolQTL: A comprehensive resource for molecular quantitative trait loci inhuman cancer.
MolQTL:人类癌症分子数量性状位点的综合资源。
- 批准号:
10933833 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
MolQTL: A comprehensive resource for molecular quantitative trait loci in human cancer.
MolQTL:人类癌症分子数量性状位点的综合资源。
- 批准号:
10181442 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
Systematic Characterization of Small Nucleolar RNAs in Cancer
癌症中小核仁 RNA 的系统表征
- 批准号:
10277525 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
Characterization of Alternative Polyadenylation in Alzheimer's Disease
阿尔茨海默病中替代多腺苷酸化的表征
- 批准号:
10363157 - 财政年份:2021
- 资助金额:
$ 41.47万 - 项目类别:
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